Processes for the preparation of rivaroxaban and intermediates thereof

ABSTRACT

This invention provides a process for the preparation of S-Rivaroxaban and/or R-Rivaroxaban comprising reacting, in the presence of a first base, a compound of Formula 9: 
                         
with a compound of Formula 8:

This is a Division of U.S. application Ser. No. 12/431,272 filed on Apr.28, 2009.

TECHNICAL FIELD

The present invention relates to the field of chemical synthesis oforganic compounds and in particular to methods for the synthesis ofRivaroxaban and intermediates thereof.

BACKGROUND

Rivaroxaban (1)(5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl}thiophene-2-carboxamide)is a low molecular weight, orally administrable anticoagulant drug. Thepharmaceutical directly inhibits the active form of serine proteaseFactor Xa (FXa). Rivaroxaban can be used for the prevention andtreatment of various thromboembolic diseases, in particular of deep veinthrombosis (DVT), pulmonary embolism (PE), myocardial infract, anginapectoris, reocclusions and restenoses after angioplasty or aortocoronarybypass, cerebral stroke, transitory ischemic attacks, and peripheralarterial occlusive diseases.

Rivaroxaban is disclosed in WO 01/47919 and has the following structure:

US2007/0149522 relates to a method for producing5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide starting from 5-chlorothiophene-2-carbonyl chloride and(2S)-3-amino-propane-1,2-diol and 4-(4-aminophenyl)-3-morpholinone.

US2007/0066611 relates to a process for preparing4-(4-aminophenyl)-3-morpholinone by reacting4-(4-nitrophenyl)-3-morpholinone with hydrogen in the presence of ahydrogenation catalyst, characterized in that the reaction is effectedin an aliphatic alcohol.

U.S. Pat. No. 7,351,823 relates to a process for preparing5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamidestarting from 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3-(2H)-dione,4-(4-aminophenyl)-3-morpholinone and 5-chlorothiophene-2-carbonylchloride.

WO 2009/023233 relates to novel compounds that are substitutedoxazolidinones derivatives and pharmaceutically acceptable saltsthereof. More specifically, this invention relates to noveloxazolidinone compounds that are derivatives of Rivaroxaban. Theinvention also provides pyrogen-free compositions comprising one or morecompounds of the invention and a carrier, along with the use of thedisclosed compounds and compositions in methods of treating diseases andcondition that are beneficially treated by administering a selectiveinhibitor of factor Xa, such as Rivaroxaban.

SUMMARY

This invention is based, in part, on preparing Rivaroxaban by reacting acompound of Formula 8a, 8b or 8c with 5-chlorothiophene-2-carboxamide ofFormula 9 in Scheme 1.

The present invention is directed to methods of preparation ofRivaroxaban, various intermediates useful in the preparation ofRivaroxaban and methods of preparation of such intermediates.

In illustrative embodiments of the present invention, Rivaroxaban andthe intermediates thereof may be prepared by an exemplary process as setout in Scheme 1. Exemplary reagents and conditions for these reactionsare disclosed herein.

In illustrative embodiments of the present invention, the (R)-enantiomerof Rivaroxaban is prepared by the processes of the present invention byreplacing the compound of Formula 4 of Scheme 1 with the (S)-enantiomer(ie. (S)-(+)-epichlorohydrin) and preparing compounds having thestereochemistry as shown in Scheme 1a.

In illustrative embodiments of the present invention, there is provideda process for the preparation of S-Rivaroxaban and/or R-Rivaroxabancomprising reacting, in the presence of a first base, a compound ofFormula 9:

with a compound of Formula 8:

wherein R⁴ is selected from the group consisting of:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl;

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring;

X is halogen; and

L² is a halogen or sulfonyloxy group.

In illustrative embodiments of the present invention, there is provideda process described herein wherein a compound of Formula 8 is a compoundof Formula 8a and/or 8aa:

In illustrative embodiments of the present invention, there is provideda process described herein wherein a compound of Formula 8 is a compoundof Formula 8b and/or 8ba:

In illustrative embodiments of the present invention, there is provideda process described herein wherein a compound of Formula 8 is a compoundof Formula 8c and/or 8ca:

In illustrative embodiments of the present invention, there is provideda process for the preparation of a compound of Formula 8a:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl;

R² and R³ when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen, the process comprising:

i. reacting, optionally in the presence of a second base, a compound ofFormula 2:

with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8a, thereby forming a compound ofFormula 5:

wherein G is as defined above for Formula 8a; and

ii. reacting the compound of Formula 5, in the presence of a third base,with a compound of Formula 4:

wherein L² is a halogen or sulfonyloxy group, thereby forming thecompound of Formula 8a.

In illustrative embodiments of the present invention, there is provideda process for the preparation of a compound of Formula 8a:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl;

R² and R³ when together form a single ring group with the N to whichthey are bonded are a heteroaryl ring; and

X is halogen, the process comprising:

i. reacting, in the presence of a fourth base, a compound of Formula 2:

with a compound of Formula 4:

wherein L² is a halogen or sulfonyloxy group, thereby forming a compoundof Formula 6:

and;

ii. reacting, optionally in the presence of a fifth base, the compoundof Formula 6 with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8a, thereby forming the compound ofFormula 8a.

In illustrative embodiments of the present invention, there is provideda process for the preparation of a compound of Formula 8c:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl;

R² and R³ when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

L² is a halogen or sulfonyloxy group, the process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 4:

wherein L² is a halogen or sulfonyloxy group; thereby forming a compoundof Formula 7:

wherein

L² is as defined for Formula 4; and

ii. reacting, in the presence of a sixth base, the compound of Formula 7with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8c, thereby forming the compound ofFormula 8c.

In illustrative embodiments of the present invention, there is provideda process for the preparation of a compound of Formula 8a:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl;

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring;

X is halogen,

the process comprising conversion of a compound of Formula 8c to thecompound of Formula 8a.

In illustrative embodiments of the present invention, there is provideda compound of Formula 5a:

wherein

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl.

In illustrative embodiments of the present invention, there is provideda compound of Formula 5a:

wherein

R¹ is alkyl or substituted alkyl.

In illustrative embodiments of the present invention, there is provideda compound of Formula 5b:

In illustrative embodiments of the present invention, there is provideda compound of Formula 6:

In illustrative embodiments of the present invention, there is provideda compound of Formula 8a:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8a1:

wherein

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted arylalkyl.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8a1:

wherein

R¹ is alkyl or substituted alkyl.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8a2:

In illustrative embodiments of the present invention, there is provideda compound of Formula 8c:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

L² is a halogen or sulfonyloxy group.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8c1:

wherein

R¹ is alkyl or substituted alkyl and L² is a halogen or sulfonyloxygroup.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8c2:

wherein

L² is a halogen or sulfonyloxy group.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8c3:

In illustrative embodiments of the present invention, there is provideda process for the preparation of a compound of Formula 8aa:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl;

R² and R³ when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen, the process comprising:

i. reacting, optionally in the presence of a second base, a compound ofFormula 2:

with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8aa, thereby forming a compound ofFormula 5:

wherein G is as defined above for Formula 8aa; and

ii. reacting the compound of Formula 5, in the presence of a third base,with a compound of Formula 4a:

wherein L² is a halogen or sulfonyloxy group, thereby forming thecompound of Formula 8aa.

In illustrative embodiments of the present invention, there is provideda process for the preparation of a compound of Formula 8aa:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl;

R² and R³ when together form a single ring group with the N to whichthey are bonded are a heteroaryl ring; and

X is halogen, the process comprising:

i. reacting, in the presence of a fourth base, a compound of Formula 2:

with a compound of Formula 4a:

wherein L² is a halogen or sulfonyloxy group, thereby forming a compoundof Formula 6a:

and;

ii. reacting, optionally in the presence of a fifth base, the compoundof Formula 6a with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8aa, thereby forming the compound ofFormula 8aa.

In illustrative embodiments of the present invention, there is provideda process for the preparation of a compound of Formula 8ca:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl;

R² and R³ when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

L² is a halogen or sulfonyloxy group, the process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 4a:

wherein L² is a halogen or sulfonyloxy group; thereby forming a compoundof Formula 7a:

wherein

L² is as defined for Formula 4a; and

ii. reacting, in the presence of a sixth base, the compound of Formula7a with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8ca, thereby forming the compound ofFormula 8ca.

In illustrative embodiments of the present invention, there is provideda process for the preparation of a compound of Formula 8aa:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl;

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; X is halogen, the processcomprising conversion of a compound of Formula 8ca to the compound ofFormula 8aa.

In illustrative embodiments of the present invention, there is provideda compound of Formula 6a:

In illustrative embodiments of the present invention, there is provideda compound of Formula 8aa:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen;

In illustrative embodiments of the present invention, there is provideda compound of Formula 8aa1:

wherein

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted arylalkyl.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8aa1:

wherein

R¹ is alkyl or substituted alkyl.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8aa2:

In illustrative embodiments of the present invention, there is provideda compound of Formula 8ca:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

L² is a halogen or sulfonyloxy group.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8ca1:

wherein

R¹ is alkyl or substituted alkyl and L² is a halogen or sulfonyloxygroup.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8ca2:

wherein

L² is a halogen or sulfonyloxy group.

In illustrative embodiments of the present invention, there is provideda compound of Formula 8ca3:

Other aspects and features of the present invention will become apparentto those ordinarily skilled in the art upon review of the followingdescription of specific embodiments of the invention in conjunction withthe accompanying figures.

DETAILED DESCRIPTION

As used herein, the term “substituted” refers to the replacement of ahydrogen atom on a compound with a substituent group. A substituent maybe a non-hydrogen atom or multiple atoms of which at least one is anon-hydrogen atom and one or more may or may not be hydrogen atoms. Forexample, without limitation, substituted compounds may comprise one ormore substituents selected from the group consisting of: R″, OR″,NR″R″′, SR″, halogen, SiR″R″′R′″, OC(O)R″, C(O)R″, CO₂R″, CONR″R′″,NR″′C(O)₂R″, S(O)R″, S(O)₂R″, CN, and NO₂.

As used herein, each R″, R′″, and R″″ may be selected, independently,from the group consisting of: hydrogen, halogen, oxygen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, andarylalkyl groups.

As used herein, the term “alkyl” by itself or as part of anothersubstituent, means, unless otherwise stated, a saturated straight orbranched chain, or cyclic hydrocarbon radical, or combination thereofhaving the number of carbon atoms designated (e.g. C₁-C₁₀ or 1- to10-membered means one to ten carbons). When there is no indication ofthe number of carbon atoms in the alkyl, it is meant, unless otherwiseindicated by context, that there are from 1 to 10 carbons. Examples ofsaturated hydrocarbon radicals include, but are not limited to, groupssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologsand isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, andthe like.

As used herein, the term “aryl” by itself or as part of anothersubstituent, means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent which can be a single ring or multiplerings (often from 1 to 3 rings) which are fused together or linkedcovalently. “Aryl” includes, but is not limited to, “heteroaryl” groups.“Heteroaryl” refers to an aryl group that contain from one to fourheteroatoms selected from N, O, and S, wherein the nitrogen and sulfuratoms are optionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl group can be attached to the remainder of themolecule through a heteroatom. Non-limiting examples of aryl andheteroaryl groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl 1,3-furyl 1,2-thienyl, 3-thienyl,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. The term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl”, is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl, etc.) including those alkylgroups in which a carbon atom containing group (e.g., a methylene group)has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc).

The present invention is directed to methods of preparation ofRivaroxaban, various intermediates useful in the preparation ofRivaroxaban and methods of preparation of such intermediates.

A person of skill in the art recognizes that by appropriate choice ofreagents, the processes of the present invention may be equally appliedto the preparation of the (R)-enantiomer of Rivaroxaban. By replacing(R)-(−)-epichlorohydrin (compound of Formula 4) of the present inventionwith (S)-(+)-epichlorohydrin, the (R)-enantiomer of Rivaroxaban isobtained. The processes of the present invention encompass preparationof both enantiomers of Rivaroxaban.

According to illustrative embodiments of the present invention, there isprovided a process for the preparation of (S)-Rivaroxaban and/or(R)-Rivaroxaban comprising reacting, in the presence of a first base, acompound of Formula 9:

with a compound of Formula 8:

wherein

R⁴ is one of the following:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring;

X is halogen; and

L² is a halogen or sulfonyloxy group.

The first base may be a strong base suitable for deprotonation of anamide. The first base may be an organometallic compound. Theorganometallic compound may be selected from the group consisting oforganomagnesium, organozinc, organosodium, organolithium compounds andmixtures thereof. The first base may be selected from the groupconsisting of alkylmagnesium halide, arylmagnesium halide, alkylzinchalide, alkyllithium, aryllithium, lithium hexaalkyldisilazide, sodiumhexaalkyldisilazide, potassium hexaalkyldisilazide, potassiumt-butoxide, sodium hydride, lithium hydride, L-selectride, superhydride,lithium amide, sodium amide, lithium dialkylamide, and mixtures thereof.The first base may be lithium hexamethyldisilazide, n-butyllithium, orpotassium t-butoxide. The first base may be combined with an inorganicsalt additive such as LiX or CuX wherein X is halogen.

The reaction of the compound of Formula 8 with the compound of Formula 9may be conducted in a first solvent. The first solvent may be a suitableaprotic organic solvent. The first solvent may be selected from thegroup consisting of alkyl ethers (e.g. tetrahydrofuran, dioxane, diethylether, methyl t-butyl ether, diisopropyl ether, butyl ether), alkylesters (e.g. ethyl acetate, isopropyl acetate), ketones (e.g. acetone,methyl ethyl ketone, methyl isobutyl ketone), aromatic, and aliphatichydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes), nitriles(e.g. acetonitrile, propionitrile, butyronitrile, and benzonitrile),N,N-dialkylamides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide,and N-methyl-2-pyrrolidinone), sulfoxides and sulfones (e.g. dimethylsulfoxide and sulfolane), halogenated hydrocarbons (e.g. dichloromethaneand dichloroethane), and mixtures thereof.

According to illustrative embodiments of the present invention, there isprovided a process for preparation of a compound of Formula 8a:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from H,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl andsubstituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising:

i. reacting, optionally in the presence of a second base, a compound ofFormula 2:

with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8a, thereby forming a compound ofFormula 5:

wherein

G is as defined above for Formula 8a; and

ii. reacting the compound of Formula 5, in the presence of a third base,with a compound of Formula 4:

wherein

L² is a halogen or sulfonyloxy group, thereby forming the compound ofFormula 8a.

In some embodiments, the compound of Formula 3 is a compound in which L¹is halogen and G is OR¹. In some embodiments the compound of Formula 3is a compound in which L¹ is chloro and R¹ is alkyl. In some embodimentsthe compound of Formula 3 is a compound in which L¹ is chloro and R¹ ismethyl. In some embodiments the compound of Formula 3 is a compound inwhich L¹ and G are imidazole.

In some embodiments the compound of Formula 4 is a compound in which L²is a sulfonyloxy group. In some embodiments the compound of Formula 4 isa compound in which L² is a toluenesulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy group. In some embodiments the compound ofFormula 4 is a compound in which L² is a halogen. In some embodimentsthe compound of Formula 4 is a compound in which L² is chloro.

The second base may be inorganic or organic. The second base may beselected from the group consisting of metal hydroxides, carbonates,phosphates, tertiary amines, and aryl amines. The second base may beselected from the group consisting of sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate,potassium carbonate, lithium carbonate, potassium phosphate, sodiumphosphate, triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, pyridine, and mixtures thereof.

The reaction of the compound of Formula 2 with the compound of Formula 3may be conducted in a second solvent. The second solvent may be selectedfrom the group consisting of alkyl ethers (e.g. tetrahydrofuran,dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butylether), alkyl esters (e.g. ethyl acetate, isopropyl acetate), ketones(e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone), aromaticand aliphatic hydrocarbons (e.g. toluene, xylenes, hexanes, andheptanes), nitriles (e.g. acetonitrile, propionitrile, butyronitrile,and benzonitrile), N,N-dialkylamides (e.g. N,N-dimethylformamide,N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides andsuit ones (e.g. dimethyl sulfoxide and sulfolane), halogenatedhydrocarbons (e.g. dichloromethane and dichloroethane), alcohols (e.g.methanol, ethanol, isopropanol, butanol), water and mixtures thereof.

The third base may be a suitable non-nucleophilic base. The third basemay be selected from the group consisting of lithiumhexamethyldisilazide, lithium dialkyl amide, sodium hydride, potassiumt-butoxide and n-butyllithium.

The reaction of the compound of Formula 5 with the compound of Formula 4may be conducted in a third solvent. The third solvent may be a suitableaprotic organic solvent. The third solvent may be selected from thegroup consisting of alkyl ethers (e.g. tetrahydrofuran, dioxane, diethylether, methyl t-butyl ether, diisopropyl ether, butyl ether), alkylesters (e.g. ethyl acetate, isopropyl acetate), ketones (e.g. acetone,methyl ethyl ketone, methyl isobutyl ketone), aromatic and aliphatichydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes), nitriles(e.g. acetonitrile, propionitrile, butyronitrile, and benzonitrile),N,N-dialkylamides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide,and N-methyl-2-pyrrolidinone), sulfoxides and sulfones (e.g. dimethylsulfoxide and sulfolane), halogenated hydrocarbons (e.g. dichloromethaneand dichloroethane), and mixtures thereof.

According to illustrative embodiments of the present invention, there isprovided a process for the preparation of a compound of Formula 8a:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising:

i. reacting, in the presence of a fourth base, a compound of Formula 2:

with a compound of Formula 4:

wherein

L² is a halogen or sulfonyloxy group, thereby forming a compound ofFormula 6:

and;

ii. reacting, optionally in the presence of a fifth base, the compoundof Formula 6 with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8a, thereby forming the compound ofFormula 8a.

In some embodiments the compound of Formula 4 is a compound in which L²is a sulfonyloxy group. In some embodiments the compound of Formula 4 isa compound in which L² is a toluenesulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy group. In some embodiments the compound ofFormula 4 is a compound in which L² is a halogen. In some embodimentsthe compound of Formula 4 is a compound in which L² is chloro.

In some embodiments the compound of Formula 3 is a compound in which L¹is halogen and G is OR¹. In some embodiments the compound of Formula 3is a compound in which L¹ is chloro and R¹ is alkyl. In some embodimentsthe compound of Formula 3 is a compound in which L¹ is chloro and R¹ ismethyl. In some embodiments the compound of Formula 3 is a compound inwhich L¹ and G are imidazole.

The fourth base may be inorganic or organic. The fourth base may beselected from the group consisting of metal hydroxides, carbonates,phosphates, tertiary amines, and aryl amines. The fourth base may beselected from the group consisting of sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate,potassium carbonate, lithium carbonate, potassium phosphate, sodiumphosphate, triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, pyridine, and mixtures thereof.

Reaction of the compound of Formula 2 with the compound of Formula 4 maybe conducted in a fourth solvent. The fourth solvent may be selectedfrom the group consisting of alkyl ethers (e.g. tetrahydrofuran, diethylether, methyl t-butyl ether, diisopropyl ether, butyl ether), alkylesters (e.g. ethyl acetate, isopropyl acetate), ketones (e.g. acetone,methyl ethyl ketone, methyl isobutyl ketone), aromatic and aliphatichydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes), nitriles(e.g. acetonitrile, propionitrile, butyronitrile, and benzonitrile),N,N-dialkylamides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide,and N-methyl-2-pyrrolidinone), sulfoxides and sulfones (e.g. dimethylsulfoxide and sulfolane), halogenated hydrocarbons (e.g. dichloromethaneand dichloroethane), alcohols (e.g. methanol, ethanol, isopropanol,butanol), water and mixtures thereof.

The fifth base may be inorganic or organic. The fifth base may beselected from the group consisting of metal hydroxides, carbonates,phosphates, tertiary amines, and aryl amines. The fifth base may beselected from the group consisting of sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate,potassium carbonate, lithium carbonate, potassium phosphate, sodiumphosphate, triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, pyridine, and mixtures thereof.

In some embodiments, the compound of Formula 2 may be treated with thecompound of Formula 4 without base to yield an intermediate of Formula7, which may or may not be isolated, before treatment with a fourth baseto yield the compound of Formula 6.

Reaction of the compound of Formula 6 with the compound of Formula 3 maybe conducted in a fifth solvent. The fifth solvent may be selected fromthe group consisting of alkyl ethers (e.g. tetrahydrofuran, dioxane,diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether),alkyl esters (e.g. ethyl acetate, isopropyl acetate), ketones (e.g.acetone, methyl ethyl ketone, methyl isobutyl ketone), aromatic andaliphatic hydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes),nitriles (e.g. acetonitrile, propionitrile, butyronitrile, andbenzonitrile), N,N-dialkylamides (e.g. N,N-dimethylformamide,N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides andsulfones (e.g. dimethyl sulfoxide and sulfolane), halogenatedhydrocarbons (e.g. dichloromethane and dichloroethane), alcohols (e.g.methanol, ethanol, isopropanol, butanol), water and mixtures thereof.

According to illustrative embodiments of the present invention, there isprovided a process for preparation of a compound of Formula 8c:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

L² is a halogen or sulfonyloxy group, the process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 4:

wherein

L² is a halogen or sulfonyloxy group; thereby forming a compound ofFormula 7:

wherein

L² is as defined for Formula 4,

and;

ii. reacting, in the presence of a sixth base, the compound of Formula 7with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8c, thereby forming the compound ofFormula 8c.

In some embodiments the compound of Formula 4 is a compound in which L²is a sulfonyloxy group. In some embodiments the compound of Formula 4 isa compound in which L² is a toluenesulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy group. In some embodiments the compound ofFormula 4 is a compound in which L² is a halogen. In some embodimentsthe compound of Formula 4 is a compound in which L² is chloro.

In some embodiments the compound of Formula 3 is a compound in which R¹is alkyl. In some embodiments the compound of Formula 3 is a compound inwhich R¹ is methyl. In some embodiments the compound of Formula 3 is acompound in which X is chloro and R¹ is methyl.

The sixth base may be inorganic or organic. The sixth base may beselected from the group consisting of metal hydroxides, carbonates,phosphates, tertiary amines and aryl amines. The sixth base may beselected from the group consisting of sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate,potassium carbonate, lithium carbonate, potassium phosphate, sodiumphosphate, triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, pyridine, and mixtures thereof.

Reaction of the compound of Formula 2 with the compound of Formula 4 maybe conducted in a sixth solvent that is the same as the fourth solventabove.

Reaction of the compound of Formula 7 with the compound of Formula 3 maybe conducted in a seventh solvent that is the same as the fifth solventabove.

According to illustrative embodiments of the present invention, there isprovided a process for the preparation of a compound of Formula 8a:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising conversion of a compound of Formula 8c to thecompound of Formula 8a.

Conversion of the compound of Formula 8c to the compound of Formula 8amay be conducted by treatment of the compound of Formula 8c with asuitable alkali halide optionally in the presence of a seventh base. Thesuitable alkali halide may be sodium iodide. The seventh base may be thesame as the sixth base above.

A compound of Formula 8b:

wherein

L² is as defined above for Formula 4, may be prepared from the compoundof Formula 7 or the compound of Formula 8c. For example, when thecompound of Formula 7 is treated with the compound of Formula 3 in thepresence of a suitable base, the cyclized compound of Formula 8b may beobtained. Similarly, the compound of Formula 8c may be converted to thecompound of Formula 8b under suitable conditions. For example, when thecompound of Formula 8c is treated with a suitable base, the compound ofFormula 8b may be obtained. Other methods for converting the compound ofFormula 7 or Formula 8c to the compound of Formula 8b are known to thoseskilled in the art.

According to illustrative embodiments of the present invention, there isprovided a process for preparation of a compound of Formula 8aa:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from H,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl andsubstituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising:

i. reacting, optionally in the presence of a second base, a compound ofFormula 2:

with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8aa, thereby forming a compound ofFormula 5:

wherein

G is as defined above for Formula 8aa; and

ii. reacting the compound of Formula 5, in the presence of a third base,with a compound of Formula 4a:

wherein

L² is a halogen or sulfonyloxy group, thereby forming the compound ofFormula 8aa.

In some embodiments, the compound of Formula 3 is a compound in which L¹is halogen and G is OR¹. In some embodiments the compound of Formula 3is a compound in which L¹ is chloro and R¹ is alkyl. In some embodimentsthe compound of Formula 3 is a compound in which L¹ is chloro and R¹ ismethyl. In some embodiments the compound of Formula 3 is a compound inwhich L¹ and G are imidazole.

In some embodiments the compound of Formula 4a is a compound in which L²is a sulfonyloxy group. In some embodiments the compound of Formula 4ais a compound in which L² is a toluenesulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy group. In some embodiments the compound ofFormula 4a is a compound in which L² is a halogen. In some embodimentsthe compound of Formula 4a is a compound in which L² is chloro.

The second base may be inorganic or organic. The second base may beselected from the group consisting of metal hydroxides, carbonates,phosphates, tertiary amines, and aryl amines. The second base may beselected from the group consisting of sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate,potassium carbonate, lithium carbonate, potassium phosphate, sodiumphosphate, triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, pyridine, and mixtures thereof.

The reaction of the compound of Formula 2 with the compound of Formula 3may be conducted in a second solvent. The second solvent may be selectedfrom the group consisting of alkyl ethers (e.g. tetrahydrofuran,dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butylether), alkyl esters (e.g. ethyl acetate, isopropyl acetate), ketones(e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone), aromaticand aliphatic hydrocarbons (e.g. toluene, xylenes, hexanes, andheptanes), nitriles (e.g. acetonitrile, propionitrile, butyronitrile,and benzonitrile), N,N-dialkylamides (e.g. N,N-dimethylformamide,N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides andsulfones (e.g. dimethyl sulfoxide and sulfolane), halogenatedhydrocarbons (e.g. dichloromethane and dichloroethane), alcohols (e.g.methanol, ethanol, isopropanol, butanol), water and mixtures thereof.

The third base may be a suitable non-nucleophilic base. The third basemay be selected from the group consisting of lithiumhexamethyldisilazide, lithium dialkyl amide, sodium hydride, potassiumt-butoxide and n-butyllithium.

The reaction of the compound of Formula 5 with the compound of Formula4a may be conducted in a third solvent. The third solvent may be asuitable aprotic organic solvent. The third solvent may be selected fromthe group consisting of alkyl ethers (e.g. tetrahydrofuran, dioxane,diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether),alkyl esters (e.g. ethyl acetate, isopropyl acetate), ketones (e.g.acetone, methyl ethyl ketone, methyl isobutyl ketone), aromatic andaliphatic hydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes),nitriles (e.g. acetonitrile, propionitrile, butyronitrile, andbenzonitrile), N,N-dialkylamides (e.g. N,N-dimethylformamide,N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides andsulfones (e.g. dimethyl sulfoxide and sulfolane), halogenatedhydrocarbons (e.g. dichloromethane and dichloroethane), and mixturesthereof. According to illustrative embodiments of the present invention,there is provided a process for the preparation of a compound of Formula8aa:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising:

i. reacting, in the presence of a fourth base, a compound of Formula 2:

with a compound of Formula 4a:

wherein

L² is a halogen or sulfonyloxy group, thereby forming a compound ofFormula 6a:

and;

ii. reacting, optionally in the presence of a fifth base, the compoundof Formula 6a with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8a, thereby forming the compound ofFormula 8aa.

In some embodiments the compound of Formula 4a is a compound in which L²is a sulfonyloxy group. In some embodiments the compound of Formula 4ais a compound in which L² is a toluenesulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy group. In some embodiments the compound ofFormula 4a is a compound in which L² is a halogen. In some embodimentsthe compound of Formula 4a is a compound in which L² is chloro.

In some embodiments the compound of Formula 3 is a compound in which L¹is halogen and G is OR¹. In some embodiments the compound of Formula 3is a compound in which L¹ is chloro and R¹ is alkyl. In some embodimentsthe compound of Formula 3 is a compound in which L¹ is chloro and R¹ ismethyl. In some embodiments the compound of Formula 3 is a compound inwhich L¹ and G are imidazole.

The fourth base may be inorganic or organic. The fourth base may beselected from the group consisting of metal hydroxides, carbonates,phosphates, tertiary amines, and aryl amines. The fourth base may beselected from the group consisting of sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate,potassium carbonate, lithium carbonate, potassium phosphate, sodiumphosphate, triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, pyridine, and mixtures thereof.

Reaction of the compound of Formula 2 with the compound of Formula 4amay be conducted in a fourth solvent. The fourth solvent may be selectedfrom the group consisting of alkyl ethers (e.g. tetrahydrofuran, diethylether, methyl t-butyl ether, diisopropyl ether, butyl ether), alkylesters (e.g. ethyl acetate, isopropyl acetate), ketones (e.g. acetone,methyl ethyl ketone, methyl isobutyl ketone), aromatic and aliphatichydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes), nitriles(e.g. acetonitrile, propionitrile, butyronitrile, and benzonitrile),N,N-dialkylamides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide,and N-methyl-2-pyrrolidinone), sulfoxides and sulfones (e.g. dimethylsulfoxide and sulfolane), halogenated hydrocarbons (e.g. dichloromethaneand dichloroethane), alcohols (e.g. methanol, ethanol, isopropanol,butanol), water and mixtures thereof.

The fifth base may be inorganic or organic. The fifth base may beselected from the group consisting of metal hydroxides, carbonates,phosphates, tertiary amines, and aryl amines. The fifth base may beselected from the group consisting of sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate,potassium carbonate, lithium carbonate, potassium phosphate, sodiumphosphate, triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, pyridine, and mixtures thereof.

In some embodiments, the compound of Formula 2 may be treated with thecompound of Formula 4a without base to yield an intermediate of Formula7a, which may or may not be isolated, before treatment with a fourthbase to yield the compound of Formula 6a.

Reaction of the compound of Formula 6a with the compound of Formula 3may be conducted in a fifth solvent. The fifth solvent may be selectedfrom the group consisting of alkyl ethers (e.g. tetrahydrofuran,dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butylether), alkyl esters (e.g. ethyl acetate, isopropyl acetate), ketones(e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone), aromaticand aliphatic hydrocarbons (e.g. toluene, xylenes, hexanes, andheptanes), nitriles (e.g. acetonitrile, propionitrile, butyronitrile,and benzonitrile), N,N-dialkylamides (e.g. N,N-dimethylformamide,N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides andsuit ones (e.g. dimethyl sulfoxide and sulfolane), halogenatedhydrocarbons (e.g. dichloromethane and dichloroethane), alcohols (e.g.methanol, ethanol, isopropanol, butanol), and mixtures thereof.

According to illustrative embodiments of the present invention, there isprovided a process for preparation of a compound of Formula 8ca:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups, are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

L² is a halogen or sulfonyloxy group, the process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 4a:

wherein

L² is a halogen or sulfonyloxy group; thereby forming a compound ofFormula 7a:

wherein

L² is as defined for Formula 4,

and;

ii. reacting, in the presence of a sixth base, the compound of Formula7a with a compound of Formula 3:

wherein

L¹ is a leaving group selected from the group consisting of halogen,imidazole, ester, C₁-C₄ alkoxy, trihalomethoxy, N-hydroxysuccinimide,p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is as defined above for Formula 8ca, thereby forming the compound ofFormula 8ca.

In some embodiments the compound of Formula 4a is a compound in which L²is a sulfonyloxy group. In some embodiments the compound of Formula 4ais a compound in which L² is a toluenesulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy group. In some embodiments the compound ofFormula 4a is a compound in which L² is a halogen. In some embodimentsthe compound of Formula 4a is a compound in which L² is chloro.

In some embodiments the compound of Formula 3 is a compound in which R¹is alkyl. In some embodiments the compound of Formula 3 is a compound inwhich R¹ is methyl. In some embodiments the compound of Formula 3 is acompound in which X is chloro and R¹ is methyl.

The sixth base may be inorganic or organic. The sixth base may beselected from the group consisting of metal hydroxides, carbonates,phosphates, tertiary amines and aryl amines. The sixth base may beselected from the group consisting of sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate,potassium carbonate, lithium carbonate, potassium phosphate, sodiumphosphate, triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, pyridine, and mixtures thereof.

Reaction of the compound of Formula 2 with the compound of Formula 4amay be conducted in a sixth solvent that is the same as the fourthsolvent above.

Reaction of the compound of Formula 7a with the compound of Formula 3may be conducted in a seventh solvent that is the same as the fifthsolvent above.

According to illustrative embodiments of the present invention, there isprovided a process for the preparation of a compound of Formula 8aa:

wherein

G is OR¹, NR²R³, or CX₃;

R¹ is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, orsubstituted aryl alkyl;

R² and R³ are either (a) two independent groups or (b) together form asingle ring group with the N to which they are bonded;

R² and R³, when independent groups; are independently selected from thegroup consisting of: H, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl and substituted arylalkyl,

R² and R³, when together form a single ring group with the N to whichthey are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising conversion of a compound of Formula 8ca to thecompound of Formula 8aa.

Conversion of the compound of Formula 8ca to the compound of Formula 8aamay be conducted by treatment of the compound of Formula 8ca with asuitable alkali halide optionally in the presence of a seventh base. Thesuitable alkali halide may be sodium iodide. The seventh base may be thesame as the sixth base above.

A compound of Formula 8ba:

wherein

L² is as defined above for Formula 4a, may be prepared from the compoundof Formula 7a or the compound of Formula 8ca. For example, when thecompound of Formula 7a is treated with the compound of Formula 3 in thepresence of a suitable base, the cyclized compound of Formula 8ba may beobtained. Similarly, the compound of Formula 8ca may be converted to thecompound of Formula 8ba under suitable conditions. For example, when thecompound of Formula 8ca is treated with a suitable base, the compound ofFormula 8ba may be obtained. Other methods for converting the compoundof Formula 7a or Formula 8ca to the compound of Formula 8ba are known tothose skilled in the art.

EXAMPLES

The following examples are illustrative of some of the embodiments ofthe invention described herein. These examples should not be consideredto limit the spirit or scope of the invention in any way.

Example 1

Preparation of methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b):N,N-Diisopropylethylamine (27.2 mL, 156.08 mmol) was added over 3 min toa stirred suspension of 4-(4-aminophenyl)-3-morpholinone (2, 25 g,130.07 mmol) in CH₂Cl₂ (750 mL). The reaction mixture was stirred atroom temperature for 15 min and methyl chloroformate (11.6 mL, 149.58mmol) was added drop-wise over 10 min. The resulting thick suspensionwas stirred for another 1 h and filtered through a Buchner funnel. Thesolid was washed with CH₂Cl₂ (2×75 mL) and dried under vacuum to obtainmethyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b, 30.92 g, 95%) asa crystalline solid.

¹HNMR (300 MHz, DMSO-d6) δ 3.66-3.69 (m, 2H), 3.67 (s, 3H), 3.93-3.97(m, 2H), 4.17 (s, 2H), 7.28 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H),9.72 (brs, 1H).

Example 2

Preparation of MethylN-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate(8a2): NaH (1.772 g, 48 mmol, 65% in mineral oil) was washed withheptane (30 mL) under a nitrogen atmosphere and DMF (30 mL) was added. Asuspension of methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b, 10g, 40 mmol) in DMF (60 mL) was added in one portion.(R)-(−)-epichlorohydrin (4.7 mL, 60, mmol) was added and the reactionmixture was heated at 60° C. for 3 h. The reaction mixture was cooled toroom temperature and diluted with a mixture of water (700 mL) and sat.aq. NH₄Cl. The aqueous layer was extracted with EtOAc (100 mL) followedby CH₂Cl₂ (3×100 mL). The combined organic layers were dried (Na₂SO₄)and evaporated. The residue was purified by flash chromatography oversilica gel (6×20 cm) using 70% EtOAc-heptane to obtain methylN-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (8a2,5.075 g, 42%) as a crystalline solid.

¹HNMR (400 MHz, CDCl₃) δ 2.55 (dd, J=5.5, 2.5 Hz, 1H), 2.82 (t, J=4.5Hz, 1H), 3.24-3.28 (m, 1H), 3.54, (dd, J=14.8, 6.1 Hz, 1H), 3.72 (s,3H), 3.77 (m, 2H), 3.98 (dd, J=14.8, 3.8 Hz, 1H), 4.03 (m, 2H), 4.33 (s,2H), 7.34 (s, 4H).

Example 3

Preparation of 4-[4-(N-(2R,3-epoxy-1-propyl)amino)phenyl]morpholin-3-one(6): R-(−)epichlorohydrin (1.3 mL, 16.5 mmol) was added to a suspensionof 4-(4-aminophenyl)-3-morpholinone (2, 2.883 g, 15 mmol) in IPA (75mL). The reaction mixture was refluxed for 20 h and a solution of NaHCO₃(1.513 g, 18 mmol) in water (30 mL) was added and reflux continued foranother 1.5 h. Solvent was evaporated using a rotary evaporator and theresidue was diluted with water (100 mL) and extracted with EtOAc (3×50mL). Combined organic extracts were dried (Na₂SO₄), evaporated and theresidue was purified by flash chromatography over silica gel (4×12 cm)using 80% EtOAc-heptane to obtain4-[4-(N-(2R,3-epoxy-1-propyl)amino)phenyl]morpholin-3-one (6, 1.675 g,46%) as a crystalline white solid.

¹HNMR (300 MHz, CDCl₃) δ 2.69 (dd, J=5.0, 2.2 Hz, 1H), 2.82 (t, J=4.3Hz, 1H), 3.20-3.27 (m, 2H), 3.51-3.58 (m, 1H), 3.67-3.71 (m, 2H),3.96-4.02 (m, 3H), 4.32 (s, 2H), 6.66 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.7Hz, 2H).

Example 4

Preparation of MethylN-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate(8a2): Methyl chloroformate (0.17 mL, 2.214 mmol) andN,N-Diisopropylethylamine (0.39 mL, 2.214 mmol) were added in that orderto a stirred and cooled (0° C.) solution of4-[4-(N-(2R,3-epoxy-1-propyl)amino)phenyl]morpholin-3-one (6, 500 mg,2.013 mmol) in MeCN (10 mL). The cooling bath was removed after 5 minand stirring continued for another 30 min. The reaction mixture wasdiluted with water (70 mL) and extracted with EtOAc (3×30 mL). Thecombined organic extracts were dried (Na₂SO₄), evaporated and theresidue was purified by flash chromatography over silica gel (2×16 cm)using 90% EtOAc-heptane to obtain methylN-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (8a2,536 mg, 87%) as a crystalline white solid.

¹HNMR (400 MHz, CDCl₃) δ 2.55 (dd, J=5.5, 2.5 Hz, 1H), 2.82 (t, J=4.5Hz, 1H), 3.24-3.28 (m, 1H), 3.54, (dd, J=14.8, 6.1 Hz, 1H), 3.72 (s,3H), 3.77 (m, 2H), 3.98 (dd, J=14.8, 3.8 Hz, 1H), 4.03 (m, 2H), 4.33 (s,2H), 7.34 (s, 4H).

Example 5

Preparation of4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3-one (7,L² is chloro): R(−)-epichlorohydrin (2.12 mL, 27.053 mmol) was added toa refluxing solution of 4-(4-aminophenyl)-3-morpholinone (2, 4.0 g,20.81 mmol) in IPA (125 mL). The mixture was refluxed for 24 h and thesolvent was evaporated in vacuo. The residue was purified by flashchromatography over silica gel (4×22 cm) using 90% EtOAc-hexane toobtain4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3-one (7,L² is chloro, 4.89 g, 83%) as a crystalline white solid. Alternativelythe crude residue can be purified by crystallization in EtOAc-hexane(2:1).

1HNMR (300 MHz, CDCl3) d 2.80 (d, J=5.1 Hz, 1H), 3.15-3.22 (m, 1H),3.33-3.38 (m, 1H), 3.57-3.71 (m, 4H), 3.96-4.05 (m, 3H), 4.13 (br s,1H), 4.17 (s, 2H), 6.60-6.65 (m, 2H), 7.07-7.11 (m, 2H).

Example 6

Preparation of methylN-(3-chloro-2R-hydroxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate(8c3): Methyl chloroformate (0.05 mL, 0.631 mmol) andN,N-diisopropylethylamine (0.09 mL, 0.5 mmol) were, added in that orderto a stirred solution of4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3-one (7,L² is chloro, 150 mg, 0.526 mmol) in MeCN (5 mL). The mixture wasstirred at room temperature for 1 h and solvent was evaporated in vacuoat 30-35° C. The residue was taken up in CH₂Cl₂ (25 mL) and washed withwater (10 mL). The organic layer was dried (Na₂SO₄), evaporated anddried under vacuum to obtain methylN-(3-chloro-2R-hydroxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate(8c3, 181 mg, ca. 100%).

1 HNMR (300 MHz, CDCl₃) d 3.45 (br s, 1H), 3.52 (dd, J=11.2, 5.5 Hz,1H), 3.60 (dd, J=11.2, 5.0 Hz, 1H), 3.67-3.80 (m, 3H), 3.70 (s, 3H),3.88-3.96 (m, 1H), 4.02-4.06 (m, 3H), 4.34 (s, 2H), 7.28-7.37 (m, 4H).

Example 7

Preparation of Rivaroxaban: n-BuLi (2.36 mL, 3.77 mmol, 1.6 M in hexane)was added drop-wise (over ca. 2-3 min) to a stirred and cooled (−10° C.)suspension of 5-chlorothiophene-2-carboxamide (9, 831 mg, 5.141 mmol) inTHF (8 mL). The cooling bath was removed after 30 min and the reactionmixture was stirred for another 30 min. MethylN-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (8a2,1.05 g, 3.427 mmol) was added as a solid in one portion. The reactionmixture was then refluxed for 5 h and the solvent evaporated in vacuo. Amixture of cold water (30 mL; ˜5° C.) and saturated aqueous NH₄Cl (10mL) was added to the damp residue. The mixture was stirred for 10 min,filtered and washed the solids with cold (˜5° C.) water (2×10 mL). Thesolid was pulped in MeOH (40 mL) at 60° C. for 1 h, concentrated to ˜10mL and cooled to room temperature. The solids were filtered, washed withcold (0° C.) MeOH (2×4 mL) and dried under vacuum to obtain Rivaroxaban(925 mg, 62%) as a crystalline solid.

Example 8

Preparation of Rivaroxaban: LiCl (17 mg, 0.391 mmol) was added to asolution of t-BuOK (42 mg, 0.359 mmol) in THF (1 mL). After stirring for30 min, 5-chlorothiophene-2-carboxamide (9, 79 mg, 0.489 mmol) wasadded. The suspension was stirred for another 30 min and methylN-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (8a2,100 mg, 0.326 mmol) was added. The reaction mixture was refluxed for 4 hand the solvent was evaporated using a rotary evaporator. A mixture ofcold water (8 mL; ˜5° C.) and saturated aqueous NH₄Cl (2 mL) was addedto the damp residue. The mixture was stirred for 10 min, filtered andwashed the solids with cold (˜5° C.) water (2×2 mL). The solid wasdissolved in MeOH (8 mL) and concentrated using a rotary evaporator to˜1 mL. The precipitated solids were filtered, washed with cold (0° C.)MeOH (0.5 mL) and dried under vacuum to obtain Rivaroxaban (44 mg, 31%)as a crystalline solid.

Example 9

Preparation of Rivaroxaban: LiHMDS (0.36 mL, 0.36 mmol, 1M in THF) wasadded dropwise to a suspension of 5-chlorothiophene-2-carboxamide (9, 95mg, 0.587 mmol) in THF (1 mL). The resulting homogeneous solution wasstirred at room temperature for 15 min and methylN-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (8a2,100 mg, 0.326 mmol) was added as a solid. The reaction mixture wasrefluxed for 3 h during which time solids separated out. The solvent wasevaporated in vacuo and a mixture of cold (5° C.) water (8 mL) plus sat.aq. NH₄Cl (2 mL) was added to the damp solids. The solids were filteredand washed with cold (5° C.) water (5 ml). The solids were dissolved in1:1 mixture of MeOH—CH₂Cl₂ (10 mL) and concentrated on a rotaryevaporator, to ˜1 mL. The precipitated solids were filtered, washed withcold (5° C.) MeOH (2×0.5 mL) and dried under vacuum to obtainRivaroxaban (90 mg, 64%) as a crystalline solid.

¹HNMR (300 MHz, CDCl₃) δ 3.59-3.62 (m, 2H), 3.69-3.73 (m, 2H), 3.85 (dd,J=8.9, 6.3 Hz, 1H), 3.95-3.99 (m, 2H), 4.16-4.22 (m, 1H), 4.19 (s, 2H),4.82-4.86 (m, 1H), 7.19 (d, J=4.2 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 7.56(d, J=8.7 Hz, 2H), 7.69 (d, J=4.2 Hz, 1H), 8.97 (t, J=5.5 Hz, 1H).

Although various embodiments of the invention are disclosed herein, manyadaptations and modifications may be made within the scope of theinvention in accordance with the common general knowledge of thoseskilled in this art. Such modifications include the substitution ofknown equivalents for any aspect of the invention in order to achievethe same result in substantially the same way. Numeric ranges areinclusive of the numbers defining the range: The word “comprising” isused herein as an open-ended term, substantially equivalent to thephrase “including, but not limited to”, and the word “comprises” has acorresponding meaning. As used herein, the singular forms “a”, “an” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a thing” includes more thanone such thing. Citation of references herein is not an admission thatsuch references are prior art to the present invention. Any prioritydocument(s) are incorporated herein by reference as if each individualpriority document were specifically and individually indicated to beincorporated by reference herein and as though fully set forth herein.The invention includes all embodiments and variations substantially ashereinbefore described and with reference to the examples and drawings.

1. A compound of Formula 5a:

wherein R¹ is alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, or substituted aryl alkyl, provided that the substituted arylis not substituted with NO₂.
 2. The compound of claim 1 wherein R¹ isalkyl or substituted alkyl.
 3. A compound of Formula 5b:


4. A compound of Formula 6:


5. A compound of Formula 8a:

wherein G is OR¹, NR²R³, or CX₃; R¹ is alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, or substituted aryl alkyl; R² and R³ areeither (a) two independent groups or (b) together form a single ringgroup with the N to which they are bonded; R² and R³, when independentgroups, are independently selected from the group consisting of: H,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl andsubstituted arylalkyl, R² and R³, when together form a single ring groupwith the N to which they are bonded, are a heteroaryl ring; and X ishalogen.
 6. A compound of Formula 8a1:

wherein R¹ is alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, or substituted arylalkyl.
 7. The compound of claim 6 whereinR¹ is alkyl or substituted alkyl.
 8. A compound of Formula 8a2:


9. A compound of Formula 8c:

wherein G is OR¹, NR²R³, or CX₃; R¹ is alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, or substituted aryl alkyl; R² and R³ areeither (a) two independent groups or (b) together form a single ringgroup with the N to which they are bonded; R² and R³, when independentgroups, are independently selected from the group consisting of: H,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl andsubstituted arylalkyl, R² and R³, when together form a single ring groupwith the N to which they are bonded, are a heteroaryl ring; and L² is ahalogen or sulfonyloxy group.
 10. A compound of Formula 8c1:

wherein R¹ is alkyl or substituted alkyl and L² is a halogen orsulfonyloxy group.
 11. A compound of Formula 8c2:

wherein L² is a halogen or sulfonyloxy group.
 12. A compound of Formula8c3:


13. A compound of Formula 6a:


14. A compound of Formula 8aa:

wherein G is OR¹, NR²R³, or CX₃; R¹ is alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, or substituted aryl alkyl; R² and R³ areeither (a) two independent groups or (b) together form a single ringgroup with the N to which they are bonded; R² and R³, when independentgroups, are independently selected from the group consisting of: H,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl andsubstituted arylalkyl, R² and R³, when together form a single ring groupwith the N to which they are bonded, are a heteroaryl ring; and X ishalogen.
 15. A compound of Formula 8aa1:

wherein R¹ is alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, or substituted arylalkyl.
 16. The compound of claim 15wherein R¹ is alkyl or substituted alkyl.
 17. A compound of Formula8aa2:


18. A compound of Formula 8ca:

wherein G is OR¹, NR²R³, or CX₃; R¹ is alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, or substituted aryl alkyl; R² and R³ areeither (a) two independent groups or (b) together form a single ringgroup with the N to which they are bonded; R² and R³, when independentgroups, are independently selected from the group consisting of: H,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl andsubstituted arylalkyl, R² and R³, when together form a single ring groupwith the N to which they are bonded, are a heteroaryl ring; and L² is ahalogen or sulfonyloxy group.
 19. A compound of Formula 8ca1:

wherein R¹ is alkyl or substituted alkyl; and L² is a halogen orsulfonyloxy group.
 20. A compound of Formula 8ca2:

wherein L² is a halogen or sulfonyloxy group.
 21. A compound of Formula8ca3:


22. A composition comprising S-Rivaroxaban and at least one of compounds8a, 8b and 8c: